Intravenous
Paf-acether (Paf, 15-80 micrograms kg-1) killed conscious Swiss mice in a dose-dependent manner, without causing platelet aggregation in the lung microvasculature, or pulmonary oedema.
Propranolol (0.01-10 mg kg-1, i.p.) potentiated the effects of an LD20 of Paf dose-dependently, while the beta 1-adrenoceptor selective antagonist,
metoprolol, was three orders of magnitude less potent in this respect.
Salbutamol (1 mg kg-1, i.p.) provided complete protection against an LD80 of Paf. High doses of
indomethacin,
aspirin,
benoxaprofen and
FPL 55712 given i.p. failed to inhibit the effects of an LD80 of Paf, while
BW 755C (50-100 mg kg-1) exerted a dose-dependent protection and
benzydamine (50 mg kg-1) and
nordihydroguaiaretic acid (200 mg kg-1) were partially active.
Dexamethasone (1-5 mg kg-1, s.c.) exerted a dose-dependent protection, when administered at least 4 h before Paf. In mice anaesthetized with
urethane, Paf (1-30 micrograms kg-1) produced
hypotension which was not clearly dose-related. The effects of the highest dose were also tested on the resistance of the lungs to inflation and found to produce bronchoconstriction. It may be concluded that pharmacological manipulation of beta 2-adrenoceptors modulates Paf-induced death in mice, while arachidonate metabolites of the
cyclo-oxygenase pathway and peptidoleukotrienes do not appear to be involved. However,
lipoxygenase products, distinct from peptidoleukotrienes, may play a role in this phenomenon. It is suggested that bronchoconstriction, probably associated with cardiovascular effects, is a major determinant of the acute toxicity of Paf in mice.